Evidence has shown that aromatase inhibitors reduce the rate of breast cancer recurrence to a greater extent than tamoxifen or placebo in postmenopausal women with hormone receptor–positive tumors. Because aromatase inhibitors block the conversion of androgens to estrogens that occurs in adipose tissue, the effect of obesity on the therapeutic effectiveness of these agents has been questioned. It has been hypothesized that a high body mass index (BMI) might reduce the effectiveness of an aromatase inhibitor. Women who are obese have higher levels of estrogen than do nonobese women, as a result of the peripheral production of estrone from androstenedione in adipose tissue. This is one of the mechanisms by which obesity may lead to the reported increase in the risk of breast cancer and breast cancer recurrence among obese postmenopausal women. Sestak et al conducted a post-hoc analysis of data from the ATAC trial (Arimidex, Tamoxifen alone or in combination) to compare the effectiveness of an aromatase inhibitor, anastrozole, with that of tamoxifen and to evaluate the effect of BMI on the effectiveness of anastrozole. The study population for the ATAC trial, a randomized, double-blind trial, consisted of postmenopausal women with early-stage breast cancer.

In the ATAC trial, patients received daily oral anastrozole 1 mg, tamoxifen 20 mg, or both. The combination arm was discontinued after 33 months of follow-up and was not included in this analysis. Patients included in this analysis (n = 4939) had hormone receptor–positive breast cancer. Median follow-up was 100 months. Mean BMI at baseline was 27.7 kg/m in the tamoxifen arm and 27.4 kg/m in the anastrozole arm.

The recurrence rate for women treated with anastrozole was 27% lower than for those treated with tamoxifen (adjusted HR, 0.73; 95% CI, 0.63−0.83; P < .001). Recurrence rates were lower with anastrozole than with tamoxifen at all BMI levels. The benefit of anastrozole over that of tamoxifen was greater in thinner women; in women with BMI <23 kg/m, the adjusted HR for recurrence was 0.64 (95% CI, 0.45−0.91), and for distant recurrences, it was 0.59 (95% CI, 0.39−0.89). In contrast, in women with BMI >35 kg/m, the adjusted HRs were 0.84 (95% CI, 0.61−1.14) and 0.96 (95% CI, 0.68−1.36), respectively. Tamoxifen was equally effective across all BMI levels, whereas anastrozole was significantly less effective in postmenopausal women with BMI >30 kg/m than in those with BMI <28 kg/m (P = .01).

This analysis of ATAC data was the first to evaluate the effect of BMI on the relative benefits of an aromatase inhibitor and tamoxifen. The results showed that anastrozole was less effective in obese women than in thin postmenopausal women for the prevention of breast cancer recurrence overall and at distant sites. Higher estrogen levels associated with obesity might lead to incomplete inhibition with anastrozole in obese women. Studies to determine if obese patients require higher doses of aromatase inhibitors would be warranted.